I asked Duke University Science Historian Seymour Mauskopf to reflect on the prospects of the end of science. Being extremely familiar with John Horgan’s book, he responded without hesitation that occasionally people make the claim that science is finished then “all hell breaks loose.” As a great communicator of science, rather than telling me, he showed me through this passage from a paper he wrote for Einstein’s Centennial at Duke University:
It seems probable that most of the grand underlying principles have now been firmly established and that further advances are to be sought chiefly in the rigorous application of these principles to all the phenomena which come under our notice. It is never safe to affirm that the future of physical science has no marvels in store which may be even more astonishing than those of the past; but, it seems probable that most of the grand underlying principles have now been firmly established and that further advances are to be sought chiefly in the rigorous application of these principles to all the phenomena which come under our notice.
Thus wrote the American physicist, Albert Michelson in 1894, just over ten years before the annus mirabilis of Albert Einstein in 1905. It is particularly ironic that it was Michelson who penned this prediction. Albert Michelson was the principal author of the Michelson-Morley experiment (1887), one of the path-breaking experiments in the entire history of physics. The problem engendered by its results would only be answered by Einstein’s theory of Special Relativity.
In fact, Michelson’s prediction proved to be a terrible underestimation of what was almost immediately to come. For the decade between this prediction and Einstein’s miracle year was the most tumultuous – and perhaps creative – decade in the history of physics. In November, 1895, Wilhelm Roentgen discovered X-rays (for which he received the first Nobel Prize awarded in physics). The following year, 1896, Henri Becquerel discovered radioactivity, the study of which was taken up the year after that by Pierre and Marie Curie. That same year (1897), J. J. Thomson established that the fluorescent rays discharged in cathode ray tubes were composed of negatively charged particles, which he named “electrons.” At about the same time (1898), Ernest Rutherford, a member of Thomson’s Cavendish Laboratory at Cambridge, embarked on his study of radioactivity and the structure of the atom.
Finally, in 1900, Max Planck opened up what would become Quantum Mechanics by positing, as a mathematical technique, that the energy in “black body” radiation was emitted in discrete units whose magnitude was proportional to the energy’s wavelength. The year 1900 hardly ended the creativity; the next few years were marked by major advances by the Curies, Rutherford, and others.
Then, in 1905, appeared, virtually out of nowhere, the most epochal of all the achievements of this frenzied decade, the great papers of the Albert Einstein, age twenty six: “A heuristic point of view concerning the production and transformation of light” (The photoelectric effect), “On the movement of small particles suspended in stationary liquids required by the molecular-kinetic theory of heat” (Brownian motion), “On the electrodynamics of moving bodies” (Special Relativity), and “Does the inertia of a body depend on its energy content?” (the inter-conversion of mass and energy according to the formula, E = mc2).
Cleverly, he would not let me pin him down on any predictions on the future, but admits that the implications of dark matter and the discovery of the rate at which the universe is expanding could lead to interesting results.
Defining Revolutions in Science
I feel it is important to clarify what constitutes a revolution in biology, chemistry, or physics and who determines this distinction. In Thomas Kuhn’s The Structure of Scientific Revolutions; he answers a more general question regarding revolutions in science. Kuhn’s model for revolutions or progress in science occurs through solving puzzles through a period of what he refers to as normal science, the beliefs commonly held by scientists. These beliefs are called paradigms which include the necessary tools for research. Students study these paradigms and become members of a specific profession or discipline.
Kuhnian model for revolutions in science
According to Kuhn, science texts present the view that the present state of science was reached by a series of individual discoveries and inventions. In contrast, Kuhn uses a punctuated equilibrium metaphor to distinguish between normal periods from revolutions in science. The search for a replacement paradigm is driven by the failure for the existing paradigm. When an anomaly occurs and normal science doesn’t work, then a revolution occurs, a new paradigm which involves a revision in existing scientific belief. Scientists then work in a different world with a new set of tools to complement the new paradigm.
Industrial revolutions have enabled the processing of data to evolve from using mainframes to super computers. Rather than using capillary electrophoresis, analytic chemists have nanochips to separate proteins. To trace lineages, evolutionary biologists can use DNA rather than fossils. In contrast to industrial revolutions, Kuhnian scientific revolutions in biology arise from paradigm shifts in how the majority of scientists view the world.
Four Waves: Molecular Biology as a Case Study
Within my area of expertise which is basic biological science, and in the context of discoveries relating to the understanding of evolution and complex diseases, I have found that discoveries are actually on the rise and scientific dogmas are not sacred, especially today.
Georges list for biological discoveries is limited to four areas:
• Pasteur’s Germ Theory (1859)
• Biochemistry (1800s)
• Darwin, Mendel, and the Modern Synthesis (1850s-1940s)
• Sociobiology (1970s)
In Kuhnian terms biochemistry is normal science. Sociobiology is questionable science as most scientists do not agree that behavior is entirely genetic.
For most of modern human existence, from the ancient civilizations through the enlightenment, religious dogma provided the explanations to puzzles. Historians and philosophers credit Aristotle with creating a branch of philosophy known as natural history in the fourth century BCE. Aristotle based his explanations for these puzzles on vitalism. Vitalists believe the processes of life are not explained by the laws of physics and chemistry, rather life is partially explained by a self-determining non-material force. Pasteur’s Germ Theory replaced spontaneous generation and helped lead to the descent of vitalism.
Originally, Mendel and Darwin’s theories were considered rivals by the science community. In 1875, Darwin proposed gemmules or particles from all parts the body traveled through the bloodstream and collected in the gonads providing a mechanism of inheritance. Using blood transfusions in rabbits, Darwin’s cousin Francis Galton showed gemmules are not transported in blood disproving Darwin’s theory of Pangenesis. Then, Mendel provided three laws of genetic inheritance. Although Mendel proposed a factor as a physical unit of inheritance, the actual genetic material remained a mystery. Four waves of discoveries in molecular biology would follow which would answer this question and many others.
(1) First wave: the search for a unit of heredity
In the 1870s, a series of educational and economic reforms took place in Germany promoting private initiative. As a result, the German government incorporated biological research in its universities. Biology became a profession and this led to a number of discoveries.
• Meischer discovered nuclein (1870)
• Walter Fleming discovered mitosis (1882)
• Weismann discovered germ cells reproduce by meiosis (1887)
• Wilhelm Waldeyer coins chromosome (1888)
• Sutton proposed the chromosomal theory of heredity (1902)
• Archibald Garrod proposed a unit of heredity produces specific proteins (1902)
• Danish biologist Johannsen coins gene (1909)
(2) Second wave: the relationship between genes and proteins
A number of Americans went to Germany for biological training until a number of universities in the United States adopted biological research in their medical and graduate schools patterned after the German system. Johns Hopkins was the first in 1876, and Harvard, the University of Chicago, and Columbia soon followed. Researchers from these schools became pioneers in the fields of genetics and molecular biology and a number of major discoveries took place.
• Thomas Hunt Morgan established genes are located on chromosomes (1910)
• Beadle and Tatum propose the one gene-one protein theory (1941)
• The Transforming Principle by Avery, MacLeod, and McCarty (1944)
• Based on Rosalind Franklin’s X-ray photo revealing the helical structure of DNA and Erwin Chargaff’s rules on nucleotide pairing, Watson and Crick established the double helical structure of DNA (1953)
• Crick and Masov formulate the central dogma (1958)
The central dogma: a linear relationship between genes and proteins
Although James Watson is the poster boy for American biology, it was Oswald Avery who made the discovery that DNA is genetic material. Dr. Joshua Lederberg, a Nobel Prize-winner and a former head of Rockefeller University noted this was the pivotal discovery of 20th-century biology and Nobel Prize nominations are complicated, but everybody including the Nobel Committee will acknowledge that this was their most significant failure. There must be 20-25 prizes that were awarded for work that depends on Avery’s seminal paper.
Following a series of discoveries, the elusive genetic code is cracked.
• Crick proposed the Adapter Hypothesis via tRNA (1955)
• Volkin and Astrachan discovered mRNA (1956)
• Crick proposed the sequence hypothesis (1958)
• Monad and Jacob discovered triplet codons (1961)
• Har Gobind Khorana and Marshall Nirenberg solve the genetic code (1966)
The first two waves of discoveries led to the genetic program consisting of genetic reductionism (genes) and genetic determinism (the central dogma).
(3) Third wave: jumping genes
From the 1960s-1980s, a third wave of discoveries took place spurred by Richard Nixon’s war on cancer. Of the numerous factors that lead to cancer, it was advances in bacterial and viral research that would attract the attention of the Nobel Committee.
• In the 1960s Tomas Lindahl identified the family of mammalian DNA ligase enzymes and their specific role for joining DNA fragments together by covalent bonding.These discoveries and bio-equipment manufacturing led to genetic engineering, the launching of the biotechnology industry in Silicon Valley, and the discussions of the feasibility of sequencing the human genome.
• In 1970, Hamilton Smith, Werner Arber, and Daniel Nathans discovered restriction enzymes which can break DNA fragments from chromosomes at specific sites. Using restriction enzymes, this is how bacteria can excise and reinsert DNA in different locations and exchange DNA. For their research they shared the Nobel Prize in Physiology or Medicine in 1978.
• While researching tumor viruses, which are capable of transforming normal cells into cancerous cells, Howard Temin, Renato Dulbecco, and David Baltimore simultaneously performed independent experiments leading to the discovery of a restriction enzyme called reverse transcriptase used by viruses to enter host genomes. For their research they shared the Nobel Prize in Physiology or Medicine in 1975.
• Barbara McClintock’s discovery of transposons referred to as jumping genes in corn is published in 1950. Her discovery of transposition did not gain acceptance in the scientific community for decades. Kuhnian revolutions require a consensus among scientists which sometimes leaves outside the box thinkers ostracized by the scientific community. Her discovery was confirmed when scientists observed transposons in other genomes and with the discovery of the gene for the enzyme transposase. Transposons encode the enzyme transposase that binds to single stranded DNA and enables the cutting and pasting of DNA within a genome. She received a belated Nobel Prize in 1983.
(4) Fourth Wave: Just the Beginning
When the public and private Human Genome Projects were completed in 2001, several prominent scientists described the human genome sequence as a metaphor to the periodic table of elements. In testimony before Congress, J. Craig Venter, the chief scientist of the private human genome project explained, the acquisition of the sequence of the human genome is just the beginning. The analysis of the human genome has led to a wave of discoveries.
Shortly following the Human Genome Project, in a number of press releases Venter reflected on how these discoveries have changed our understanding of DNA in relation to heredity, evolution, and diseases.
Since the June 26, 2000 announcement our understanding of the human genome has changed in the most fundamental ways. The finding that we have far fewer genes than expected suggests that environmental influences play a greater role in our development than was previously thought. The small number of genes—30,000 (later revised to 24,000) instead of 140,000—supports the notion that we are not hard-wired. We now know that the environment acting on these biological steps may be the key in making us what we are. Likewise the remarkably small numbers of genetic variations that occur in genes again suggest a significant role for environmental influences in developing each of our uniqueness.Leading up to the HGP, scientists estimated the number of human protein coding genes was over 100,000 equal to the number of proteins. One of the most startling discoveries of the Human Genome Project was that a very small percentage of the roughly three billion nucleotide bases in the human genome encode instructions for the synthesis of proteins. We now know protein-coding DNA sequences comprise an estimated 2-3 percent of the human genome.
More than two thirds of these are alternative splicing genes, which code for more than one protein, and sometimes many more. We now know that the notion that one gene leads to one protein and perhaps one disease is false. One gene leads to many different products. Those products—proteins—can change dramatically after they are produced. We know that regions of the genome that are not genes may be the key to the complexity we see in humans.
There are two fallacies to be avoided, determinism, the idea that all characteristics of a person are hard-wired by the genome; and reductionism, that now the human sequence is completely known, it is just a matter of time before our understanding of gene functions and interactions will provide a complete causal description of human variability.
Researchers have discovered the functions of some of the so-called junk DNA. This non-coding DNA is classified into several categories: repeat sequences, parasitic DNA, regulatory genes, pseudogenes or loss of function genes, and small interfering RNAs called microRNAs. MicroRNAs are roughly 20-25 nucleotides that are encoded by genes which bind to mRNAs and degrade them before they are translated into proteins. Parasitic DNA is derived from viruses and bacteria and accounts for over 40% of the human genome.
From Aristotle to the present our current understanding of heredity, human differentiation, and diseases has progressed from vital forces, particles, and units to a systems model.
The current cybernetic relationship between genes and proteins
The Next Revolution in Biology
Kuhn’s model for revolutions in science begins with puzzles. For those that are not convinced that numerous breakthroughs in biology are imminent, consider these hot topics in biology which are discussed in more detail in my forthcoming book.
• With all the talk about genomics and cures for diseases, where are the cures for bird flus, obesity, and behavioral disorders? Although the discovery of the first human genes for breast cancer, Huntington’s disease, and cystic fibrosis occurred in the 1980s, a proof of concept for curing diseases has yet to materialize using genes. Where are all the blockbuster drugs and cures based on personalized medicine? Can you name a DNA vaccine?The mindset that the end of science is near can lead to a self fulfilling prophecy. The belief in vitalism delayed our understanding of plagues, heredity, and evolution. The genetic program led to eugenics and delayed our understanding of the biological mechanisms for cell differentiation and speciation, and complex diseases. Will the lack of understanding on how culture and technology are part of what it means to be human as revealed through niche construction prohibit the use of voluntary genetic enhancements?
• Although genomics researchers expected to cure diseases, they discovered that 2-3% of the genome is protein coding and haplotypes. Haplotypes are SNPs that are inherited together which contradicts Mendel’s Law of Independent Assortment and provides the basis of understanding human differentiation through niche construction. Spencer Well’s Human Genographic Project is almost complete and will provide direction for this type of research.
• Craig Venter’s work with the synthetic biology and the minimal genome and Mark Bedau’s work with protocells have the potential not only for useful products but for better understanding of the basic science of how cells work and emergent properties.
• Researchers gave a boost to developmental biology in the past two decades with evodevo, epigenetics, and the epigenome project; however, this branch of biology is in its infancy.
• and for the protein folding problem, researchers don’t even know what we don’t know. In the early 1900s, researchers in New Guinea discovered a fatal disease called Kuru with symptoms including trembling and fever. Scientists believe Kuru’s mode of transmission is a cannibalistic ritual in the Fore tribe of consuming deceased relative’s brains. In 1997, Dr. Stan Prusiner received the Nobel Prize in Medicine or Physiology for his 1982 discovery and later isolation of proteins which he coined prions (proteinaceous infectious particles) which are responsible for Kuru and also Mad Cow Disease. Normal proteins have the same amino acids as prions, but they fold differently. When a prion invades the brain, it refolds normal brain proteins to match its own infectious three-dimensional shape setting up a chain reaction.
Acknowledgement:
I would like to thank Seymour Mauskopf for taking time out this summer from writing a biography of Alfred Nobel and preparing for classes this fall to give his reflections on the end of science. As a scholar in the history of science, specializing in physics and chemistry, he has taught for over fifty years at Duke University and held numerous administrative positions with the university, and works with Phi Beta Kappa students.
I would also like to thank him for the privilege of sitting in on his classes as well as asking me to guest lecture on cutting edge biology. For the past several years I have worked with Dr. Mauskopf hammering out the first section of my forthcoming book which discusses revolutions in biology and how they inform current public policy issues related to genetics. These exchanges have more than compensated for being forced to listen to his piano playing and being thrown out of his office on numerous occasions.